Diseases such as schizophrenia and Alzheimer's disease are marked by cognitive deficits for which there are to date no effective treatments. Drugs that activate the nicotinic acetylcholine receptor (nAChR) en- hance cognition, most robustly attentional functions. Non-selective nAChR agonists such as the prototypical agonist nicotine have a broad effects profile that includes unwanted side effects. The development of nAChR agonists selective for subtypes of the nAChR has had limited success in maximizing therapeutic and reducing side effects. The overall goal of the present proposal is to generate the knowledge upon which to base a more targeted development of nAChR agents with clinically significant cognitive-enhancing effects. Previous drug development efforts have focused on agonists of the two most widely expressed nAChR subtypes, reflecting the fact that the specific systems and mechanisms mediating the sought-after effects are largely unknown. This project is aimed at identifying the systems and mechanisms through which nAChR agents enhance attentional functions. Employing analogous human and rodent paradigms that we have shown to be reliably sensitive to the attention-enhancing effects of nicotine, this project consists of a series of mutually informative pharmacological characterization studies in healthy human never-smokers and rats. Aim 1 is to potentiate the attention-enhancing effects of nAChR agonism with Allosteric Poten- tiating Ligands (APLs). Interaction studies with low-dose nicotine (as a model agonist) and galantamine will be conducted in humans and rats, and in rats with novel, more selective APLs. Aim 2 is to evaluate the attention-enhancing properties of ultra low-dose nAChR antagonism, suggested by our previous preclinical findings. Studies in humans and rats with the nAChR antagonist mecamylamine will be accompanied by preclinical experiments employing more selective nAChR antagonists, and followed by pharmacological interaction studies to determine the secondary neurotransmitter system(s) involved. Aim 3 is to determine the secondary system(s) mediating the attention-enhancing properties of nAChR agonists. Following our previous preclinical findings, we will aim at antagonizing the attention-enhancing effects of nicotine in humans with a -adrenoceptor antagonist. Concurrent preclinical experiments will aim at reversing attentional effects of nicotine with noradrenergic, glutamatergic, GABAergic, glycinergic, and histaminergic antagonists at doses devoid of effects by themselves. The resulting knowledge would enable drug development efforts to focus on nAChR subtypes expressed more selectively on those system(s) that mediate effects on attention. Such agents would have reduced unwanted and potentially larger therapeutic effects. Evaluating benefits of APLs and ultra low-dose antagonism diversifies strategies of nAChR modulation with the aim of producing larger effects. The integration of human and rodent findings will facilitate their translation into clinical practice. Overall, the project is expectedto result in nAChR agents with greater clinical potential.